The present invention relates to novel xcex1-hydroxy, amino, and halo derivatives of xcex2-sulfonyl hydroxamic acids, to pharmaceutical compositions containing them, and to the method of using them. The compounds of the invention are inhibitors of matrix metalloproteinases involved in tissue degradation.
Loss of connective tissue integrity occurs in many disease processes, including osteoarthritis, rheumatoid arthritis, septic arthritis, osteopenias such as osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulceration, dermal ulceration, gastric ulceration, inflammation, asthma and other diseases related to connective tissue degradation. Although there is a high incidence of these diseases in the developed world, there is no treatment that prevents the tissue damage that occurs. Considerable lines of scientific evidence indicate that uncontrolled connective matrix metalloproteinase (MMPs) activity is responsible for the damage, and as a consequence the inhibition of these enzymes has become the target for therapeutic intervention (see Matrisian, L. M., Bases, Vol. 14, pp 445-463 (1992); Emonard, H. et al., Cellular and Molecular Biology, Vol. 36, pp 131-153 (1990); Docherty, A J. P. et al., Annals of the Rheumatic, Vol. 49, pp 469-479 (1990)).
Hydroxamic acid derivatives are a class of known therapeutically active MMPs inhibitors and there are numerous references in the art disclosing a variety of hydroxamic acid derivatives. For example, European Patent Publication No. 0,606,046 A1 discloses arylsulfonamido-substituted hydroxamic acids useful as matrix metalloproteinase inhibitors. International Publication Nos. WO 95/35275 and WO 95/35276 disclose sulfonamide hydroxamic acid and carboxylic acid derivatives useful as matrix metalloproteinases inhibitors. All these references relate to sulfonamide hydroxamic acids. The compounds of this invention are novel and distinct from all other sulfonamide hydroxamic acids in that the usual nitrogen atom is replaced by a carbon atom. The invention provides sulfonyl hydroxamic acid derivatives.
The compounds of the present invention inhibit various enzymes from the matrix metalloproteinase family, predominantly stromelysin and gelatinase, and hence are useful for the treatment of matrix metallo endoproteinase diseases such as osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulceration, dermal ulceration, gastric ulceration, inflammation, asthma, and other diseases related to connective tissue degradation.
The European Patent Application No. EP 0780 386 A1 discloses matrix metalloproteinases inhibitors useful in the treatment of mammals having disease states alleviated by the inhibition of such matrix metalloproteinases.
International Publication No. WO 97/24117 discloses substituted aryl, heteroaryl, arylmethyl or heteroarylmethyl hydroxamic acid compounds especially useful for inhibiting the production or physiological effects of TNF in the treatment of a patient suffering from a disease state associated with a physiologically detrimental excess of tumor necrosis factor (TNF).
International Patent Application No. PCT/US97/16348 discloses xcex2-sulfonyl hydroxamic acids as matrix metalloproteinases inhibitors.
The compounds of the present invention are novel and distinct from the above hydroxamic acids in that they have a hydroxy, amino group or fluoro on the xcex1-position and two hydrogen atoms at the xcex2-position of the hydroxmate group.
The present invention provides novel compounds of formula I 
or pharmaceutical acceptable salts thereof wherein:
R1 is
a) C4-12 alkyl,
b) C4-12 alkenyl,
c) C4-12 alkynyl,
d) xe2x80x94(CH2)hxe2x80x94C3-8 cycloalkyl,
e) xe2x80x94(CH2)h-aryl,
f) xe2x80x94(CH2)h-aryl substituted with C1-4 alkyl, C1-4 alkoxy, phenyl, C1-4 phenoxy, het, halo, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94CN, or xe2x80x94N(C1-4 alkyl)2,
g) xe2x80x94(CH2)h-het, or
h) xe2x80x94(CH2)h-het substituted with C1-4 aLkyl, phenyl, C1-4 phenoxy, het, or halo;
R2 is
a) C1-2 alkyl,
b) C1-2 alkyl substituted with one to three halo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94N(R3)2, xe2x80x94SR3, or OH,
c) C2-12 alkenyl,
d) C2-12 alkenyl substituted with one to three halo, xe2x80x94CN, xe2x80x94NO2, or xe2x80x94CF3,
e) C2-12 alkynyl,
f) C2-12 alkynyl substituted with one to three halo, xe2x80x94CN, xe2x80x94NO2, or xe2x80x94CF3,
g) xe2x80x94(CH2)hxe2x80x94C3-8 cycloalkyl,
h) xe2x80x94(CH2)hxe2x80x94C3-8 cycloalkyl substituted with one to three C1-4 alkyl, C1-4 alkoxy, or halo,
i) xe2x80x94(CH2)hxe2x80x94C3-8 cycloalkenyl,
j) xe2x80x94(CH2)hxe2x80x94C3-8 cycloalkenyl substituted with one to three C1-4 alkyl, C1-4 alkoxy, or halo,
k) xe2x80x94(CH2)h-aryl,
l) xe2x80x94(CH2)h-aryl substituted with one to three C1-4 alkyl, C1-4 alkoxy, xe2x80x94CF3xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94N(R3)2, xe2x80x94SR3, xe2x80x94SO2(C1-4 alkoxy), xe2x80x94C(xe2x95x90O)R3, or xe2x80x94NC(xe2x95x90O)R3,
m) xe2x80x94(CH2)h-aryl substituted with one to five halo,
n) xe2x80x94(CH2)h-het,
o) xe2x80x94(CH2)h-het substituted with one to two C1-4 alkyl, or halo,
p) xe2x80x94(CH2)hxe2x80x94Q,
q) xe2x80x94(CH2)hxe2x80x94Q substituted with one to three C1-4 alkyl, C1-4 alkoxy, halo, or phenyl,
r) xe2x80x94(CH2)ixe2x80x94Xxe2x80x94R4, optionally the xe2x80x94(CH2)ixe2x80x94 chain can be substituted withg one to with C1-4 alkyl or phenyl, which in turn can be substituted with one to three halo or C1-4 alkyl, or
s) xe2x80x94(CH2)hCHR5R6;
R3 is
a) H,
b) C3-6 cycloalkyl,
c) C1-4 alkyl,
d) xe2x80x94(CH2)h-phenyl, or
e) xe2x80x94(CH2)h-phenyl substituted with one to three C1-4 alkyl, C1-4 alkoxy, or halo;
X is
a) xe2x80x94Oxe2x80x94,
b) xe2x80x94S(xe2x95x90O)jxe2x80x94,
c) xe2x80x94NR7xe2x80x94,
d) xe2x80x94S(xe2x95x90O)2NR8xe2x80x94, or
e) xe2x80x94C(xe2x95x90O)xe2x80x94;
R4 is
a) H,
b) C1-8 alkyl,
c) xe2x80x94(CH2)h-phenyl,
d) xe2x80x94(CH2)h-phenyl substituted with one to three C1-4 alkyl, C1-4 alkoxy, phenyl, C1-4 phenoxy, het, halo, xe2x80x94NO2, or xe2x80x94CN, or
e) xe2x80x94(CH2)h-het;
R5 is
a) C1-4 alkyl, or
b) xe2x80x94C(xe2x95x90O)R3;
R6 is
a) xe2x80x94C(xe2x95x90O)R3, or
b) xe2x80x94(CH2)hC(xe2x95x90O)R3;
R7 is
a) H,
b) C1-4 alkyl,
c) xe2x80x94(CH2)h-phenyl,
d) xe2x80x94(CH2)h-phenyl substituted with one to three C1-4 alkyl, C1-4 alkoxy, or halo,
e) xe2x80x94(C(xe2x95x90O)xe2x80x94xe2x80x94R3,
f) xe2x80x94S(xe2x95x90O)2R3, or
g) xe2x80x94C(xe2x95x90O)OR3;
R8 is
a) C1-4 alkyl,
b) xe2x80x94(CH2)h-phenyl, or
c) xe2x80x94(CH2)h-phenyl substituted with one to three C1-4 alkyl, C1-4 alkoxy, or halo;
Y is
a) xe2x80x94OH,
b) xe2x80x94NR9R10, or
c) fluoro;
R9 and R10 are the same and different and are
a) H,
b) xe2x80x94C(xe2x95x90O)xe2x80x94R3,
c) xe2x80x94C(xe2x95x90O)xe2x80x94OR3, or
d) xe2x80x94C(xe2x95x90O)xe2x80x94
NHR3;
aryl is monocarbocyclic, or bicarbocyclic aromatic moiety;
het is 5- to 10-membered unsaturated monomonocyclic or bicyclic heterocyclic moiety having one to three atoms selected from the group consisting of oxygen, nitrogen, and sulfur;
Q is 5- to 10-membered saturated monocyclic or bicyclic heterocyclic moiety having one to two atoms selected from the group consisting of oxygen, nitrogen, and sulfur; aryl, het, C,1-12 alkyl, C1-4 alkyl C2-12 alkenyl, C2-12 alkynyl, xe2x80x94C3-8 cycloalkyl, xe2x80x94C3-6 cycloalkenyl, and phenyl being optionally substituted; h is 0, 1, 2, 3, 4, 5, or 6; i is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; j is 0, 1, or 2; and with the following provisos: a) where R2 is C1-6 alkyl, Y is other than xe2x80x94NR9R10, b) where h is 0, het and Q are attached to the xcex1-position via carbon atom of heterocyclic moiety.
The compounds of the present invention inhibit various enzymes from the matrix metalloproteinase family, predominantly stromelysin and gelatinase, and hence are useful for the treatment of matrix metallo endoproteinase diseases.
As stated above, aryl, het, C1-4 alkyl, C1-12alkyl, C2-12 alkenyl, C2-12 alkynyl, xe2x80x94C3-8 cycloalkyl, xe2x80x94C3-8 cycloalkenyl, Q and phenyl may be substituted as appropriate. Aryl is preferably substituted with C1-4 alkyl, C1-4 alkoxy, phenyl, O-phenyl, het, O-het, halo such as fluoro, chloro, bromo, OH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3, xe2x80x94N(R3)2 such as xe2x80x94N(C1-4 alkyl)2, xe2x80x94SR3, xe2x80x94SO2(C1-4 alkoxy), xe2x80x94(CH2)h-het; xe2x80x94C(xe2x95x90O)R3 or xe2x80x94NHC(xe2x95x90O)R3; het is preferably substituted with C1-4 alkyl, pheny, phenoxy or halo; C1-12 alkyl is preferably substituted with one to three halo, CN, xe2x80x94NO2 or CF3; N(R3)2 such as xe2x80x94N(C1-4 alkyl)2, xe2x80x94SR3 or xe2x80x94OH; C2-12 alkenyl, and C2-12 alkynyl are preferably substituted with one to three halo, CN, xe2x80x94NO2 or xe2x80x94CF3; C3-8 cycloalkyl and C3-8 cycloalkenyl are preferably substituted with one to three C1-4 alkyl, C1-4 alkoxy or halo; Q is preferably substituted with one to three C1-4 alkyl, C1-4 alkoxy, halo, oxo or phenyl; phenyl is preferably substituted with one to three C1-4 alkyl, C1-4 alkoxy, phenyl, phenoxy, het, halo, xe2x80x94NO2 or xe2x80x94CN.
More preferably, in the meanings of R1, the optional substituents of xe2x80x94(CH2)h-aryl are selected from C1-4 alkyl, C1-4 alkoxy, phenyl, O-phenyl, het, O-het, halo, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94CN, or xe2x80x94N(C1-4 alkyl)2; the optional substituents of xe2x80x94(CH2)h-het are selected from C1-4 alkyl, phenyl, phenoxy, het, or halo; in the meanings of R2, the optional substituents of C1-12 alkyl are one to three halo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94N(R3)2, xe2x80x94SR3, or OH; the optional substituents of C2-12 alkenyl and C2-12 alkynyl are one to three halo, xe2x80x94CN, NO2, or xe2x80x94CF3; the optional substituents of xe2x80x94(CH2)h-C3-8 cycloalkyl and xe2x80x94(CH2)h-C3-8 cycloalkenyl are one to three C1-4 alkyl, C1-4 alkoxy, or halo; the optional substituents of xe2x80x94(CH2)h-aryl are one to three C1-4 alkyl, C1-4 alkoxy, xe2x80x94CF3xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94N(R3)2, xe2x80x94SR3, xe2x80x94SO2(C1-4 alkoxy), xe2x80x94(xe2x95x90O)R3, xe2x80x94NHC(xe2x95x90O)R3, one to five halo; the optional substituents of xe2x80x94(CH2)h-het are one to two C1-4 alkyl, or halo; the optional substituents of xe2x80x94(CH2)h-Q are one to three C1-4 alkyl, C1-4 alkoxy, halo, oxo or phenyl; in the meanings of R3 the optional substituents of xe2x80x94(CH2)h-phenyl are one to three C1-4 alkyl, C1-4 alkoxy, or halo; in the meanings of R4 the optional substituents of xe2x80x94(CH2)h-phenyl are one to three C1-4 alkyl, C1-4 alkoxy, phenyl, phenoxy, het, halo, xe2x80x94NO2, xe2x80x94CNxe2x80x94; in the meanings of R7 and R8 the optional substituents of xe2x80x94(CH2)h-phenyl are one to three C1-4 alkyl, C1-4 alkoxy, or halo. In the meanings of R2, the preferred substituent(s), when present, of the xe2x80x94(CH2)ixe2x80x94 chain are one or two C1-4 alkyl, more preferably one or two methyl groups.
For the purpose of the present invention, the carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety; i.e., the prefix Cij defines the number of carbon atoms present from the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d, inclusive. Thus, C1-4 alkyl refers to alkyl of one to four carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and isomeric forms thereof.
The terms xe2x80x9cC1-4 alkylxe2x80x9d, xe2x80x9cC4-8 alkylxe2x80x9d, xe2x80x9cC1-12 alkylxe2x80x9d, and xe2x80x9cC1-18 alkylxe2x80x9d refer to an alkyl group having one to four, four to eight, one to twelve, or one to eighteen carbon atoms respectively such as; for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and their isomeric forms thereof, preferably an alkyl group of R1 having four to eight carbon atoms, and an alkyl group of R2 having one to eight carbon atoms.
The terms xe2x80x9cC2-12 alkenylxe2x80x9d and xe2x80x9cC4-8 alkenylxe2x80x9d refer to at least one double bond alkenyl group having two to twelve carbon atoms respectively such as; for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, heptdienyl, octenyl, octadienyl, octatrienyl, nonenyl, undecenyl, dodecenyl, and their isomeric forms thereof, preferably an alkenyl group of R1 having four to eight carbon atoms, and an alkenyl group of R2 having two to eight carbon atoms.
The term xe2x80x9cC2-12 alkynylxe2x80x9d refers to at least one triple bond alkynyl group having two to twelve carbon atoms such as; for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, octadiynyl, octatriynyl, nonynyl, nonediynyl, and their isomeric forms thereof, preferably an alkynyl group of R1 having four to eight carbon atoms, and an alkenyl group of R having two to eight carbon atoms.
The term xe2x80x9cC3-8 cycloalkylxe2x80x9d refers to a cycloalkyl having three to eight carbon atoms such as; for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and their isomeric forms thereof, preferably a cycloalkyl group having five or six carbon atoms.
The term xe2x80x9cC3-8 cycloalkenylxe2x80x9d refers to a cycloalkenyl having three to six or three to eight carbon atoms such as; for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and their isomeric forms thereof, preferably a cycloalkyl group having five or six carbon atoms.
The terms xe2x80x9cC1-4 alkoxyxe2x80x9d, xe2x80x9cC1-6 alkoxyxe2x80x9d, and xe2x80x9cC1-8 alkoxyxe2x80x9d refer to an alkyl group having one to four, one to six, or one to eight carbon atoms respectively attached to an oxygen atom of hydroxyl group such as; for example, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy and their isomeric forms thereof.
The term xe2x80x9carylxe2x80x9d refers to monocarbocyclic or bicarbocyclic aromatic moiety such as; for example phenyl, naphthyl, and biphenyl. Each of these moieties may be substituted as appropriate. Aryl is preferably phenyl or phenyl substituted with C1-4 alkyl, C1-4 alkoxy, fluoro, chloro, bromo, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94N(C1-4 alkyl)2, xe2x80x94C(xe2x95x90O)R3, or xe2x80x94NC(xe2x95x90O)R3.
The term xe2x80x9chetxe2x80x9d refers to a 5- to 10-membered unsaturated moncyclic or bicyclic heterocyclic moiety having one or more atoms selected from the group consisting of oxygen, nitrogen, and sulfur such as; for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyl, 3quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4isoquinolyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1-phthalazinyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isochiazole, 5-isothiazole, 2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl, benzoisothiazole, benzoisoxazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1-indolyl, 1-indazolyl, 2-isoindolyl, 1-purinyl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, preferably pyridyl, quionlinyl, pyrrolyl, thienyl, thiazolyl, or indolyl. Each of these moieties may be substituted with one to two C1-4 alkyl, xe2x80x94NO2, fluoro, chloro, or bromo as appropriate.
The term xe2x80x9cQxe2x80x9d refers to a 5- to 10-membered saturated monocyclic or bicyclic heterocyclic moiety having one to two atoms selected from the group consisting of oxygen, nitrogen, and sulfur such as, for example, piperidinyl, 2-, 3-, or 4-piperidinyl, [1,4]piperazinyl, 2- or 3-morpholinyl, thiomorpholinyl, dioxolanyl, imidazolidinyl, [1,3]oxathiolanyl, [1,3]oxazolidinyl, pyrrolidinyl, butyrolactonyl, butyrolactamyl, succinimidyl, glutarimidyl, valerolactamyl, 2,5-dioxo-[1,4]-piperazinyl, pyrazolidinyl, 3-oxopyrazolidinyl, 2-oxo-imidazolidinyl, 2,4dioxo-imridazolidinyl, 2-oxo-[1,3]-oxazolidinyl, 2,5-dioxo-[1,3]-oxazolidinyl, isoxazolidinyl, 3-oxo-isoxazolidinyl, [1,3]-thiazolidinyl, 2- or 4-oxo-[1,3]-thiazolidinyl, preferably butyrolactamyl, succinimidyl, glutarimidyl, valerolactamyl, 2,5-dioxo-[1,4]-piperazinyl, 3-oxopyrazolidinyl, 2-oxo-imidazolidinyl, 2,4-dioxo-imidazolidinyl, 2-oxo-[1,3]-oxazolidinyl, 2,5-dioxo-[1,3]-oxazolidinyl, 3-oxo-isoxazolidinyl, 2- or 4-oxo-[1,3]-thiazolidinyl.
The term halo refers to fluoro, chloro, bromo, or iodo, preferably fluoro, chloro, or bromo.
The compounds of the present invention can be converted to their salts, where appropriate, according to conventional methods.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to acid addition salts useful for administering the compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citric acid, 2-hydroxyethyl sulfonate, fumarate and the like. These salts may be in hydrated form. Some of the compounds of this invention may form metal salts such as sodium, potassium, calcium and magnesium salts and these are embraced by the term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d.
The compounds of formula I of this invention contain a chiral center at the xcex1-position of hydroxamic acids, as such there exist two enantiomers or a racemic mixture of both. This invention relates to both the enantiomers, as well as mixtures containing both the isomers. In addition, depending on the substituents, additional chiral centers and other isomeric forms may be present in any of the R2 groups, and this invention embraces all possible stereoisomers and geometric forms in this group.
R1 is preferably n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 3-methybutyl, n-hexyl, n-heptyl, n-octyl, phenyl, 4-methylphenyl, 4-ethylphenyl, 4-tert-butylphenyl, 4-isopropylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-butyloxyphenyl, benzyl, 4-phenylbenzyl, 2-, 3-, or 4-fluorobenzyl, 2-, 3-, 4-chlorobenzyl, 2-, 3-, 4-bromobenzyl, and 4-ethoxybenzyl. More preferably R1 is n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, phenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-butoxyphenyl, benzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-ethoxybenzyl, 4-phenylphenyl or 4-n-butylphenyl. More preferably R1 is 4-phenylphenyl, 4-n-butylphenyl, 4-fluorophenyl, or 4-methoxyphenyl 4 butoxyphenyl, benzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-ethoxybenzyl, 4-phenylphenyl, 4-n-butylphenyl, biphenyl, 4-chlorobiphenyl, 4-phenoxyphenyl, 4-(pyrid-4-yl)phenyl, and 4-(pyrid-4-yl)oxyphenyl.
R2 is preferably 1-cyano-1-phenyl methyl, 2-cyano ethyl, 2-phenylethyl, 2-bromo-2-phenylethyl, 2-bromoethyl, propyl, isopropyl, 3-chloropropyl, 3-bromopropyl, n-butyl, isobutyl, 3-methylbutyl, 1-methylpropyl, tert-butyl, n-pentyl, 3-methybutyl, n-hexyl, n-heptyl, n-octyl, n-hexadecyl, n-octadecyl, 2-propenyl, 2-propynyl, 3-butenyl, 4-pentenyl, 3-butenynyl, 4-pentenynyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 4-cyclohexylbutyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminopropyl, phenylaminomethyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-nitrophenyl, 4-ethoxyphenyl, benzyl, 4-methylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, and 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-ethoxybenzyl, 4-nitrobenzyl, methylcarbonyl, 1-methylcarbonyl, methyl, N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesultonyl) methyl]-3-(N-(4-methoxybenzenecarbonyl)amino)-propionamide, N-Hydroxy-2-hydroxy-2-(1-methylhydantoin-3-yl)methyl]-3-(4-methoxybenzenesulfonyl)propionamide, N-Hydroxy-2-hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-(4-methoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(1-methylhydantoin-3-yl)methyl-3-(4-butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(1-butylhydantoin-3-yl)methyl-3-(4-4 butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-(4-butoxybenzenesalfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(methylthio)methyl-3-(4-butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(phenylthio)methyl-3-(4-butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(benzylthio)methyl-3-(4-butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(pyrid-2-yl)thiomethyl-3-(4-butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-(4-butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(2-aminothiazol-5-yl)thiomethyl-3-(4-butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-(4-butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(1-methyl-1H-imidazol-2-yl)thiomeihyl-3-(4-butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(1-methyltetrazol-5-yl)thiomethyl-3-(4-butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-(4-butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(pyrid-2-yl)methylthiomethyl-3-(4-butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(1-methyl-1H-imidazol-2-yl)methylthiomethyl-3-(4-butoxybenzenesulfonyl)propionarnide; N-Hydroxy-2-hydroxy-2-(1-benzyl- I H-imidazol-2-yl)methylthiomethyl-3-(4butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(5-methylisoxazol-3-yl)methylthiomethyl-3-(4-butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(2-benzylthio-2-methylethyl)-3-(4-butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-[2-(pyrid-2-yl)thio-2-methyleth yl]-3-(4-butoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(1-methylhydantoin-3-yl)methyl-3-(4-chlorobiphenyl-sulfonyl) propionamide; N-Hydroxy-2-hydroxy-2-(1-butylhydantoin-3-yl)methy-3-(4-chlorobiphenylsulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-(4-chlorobiphenylsulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(phenylthio)methyl-3-(4-chlorobiphenylsulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-benzylthio)methyl-3-(4-chlorobiphenylsulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(pyrid-2-yl)methylthiomethyl-3-(4-chlorobiphenylsulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(5-methylisoxazol-3-yl)methylthiomethyl-3-(4-chlorobiphenylsulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-[2-(1-methylhydantoin-3-yl)methylethyl]-3-(4-chlorobiphenylsulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-[2-(pyril-2-yl)thio-2-methylethyl]-3-(4-chlorobiphenylsulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(1-methylhydantoin-3-yl)methyl-3-(4-phenoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(1-butylhydantoin-3-yl)methyl-3-(4-phenoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-(4-phenoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(1-benzylhydantoin-3-yl)methyl-3-(4-phenoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(phenylthio)methyl-3-(4-phenoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(benzylthio)methyl-3-(4-phenoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(pyrid-2-yl)methylthiomethyl-3-(4-phenoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(1-methyl-1H-imidazol-2-yl)methylthiomethyl-3-(4-phenoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-[2-(1-methylhydantoin-3-yl)-2-methylethyl-3-(4-phenoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-[2-(1-methyl-1H-imidazol-2-yl)thio-2-methylethyl]-(4-phenoxybenzenesulfonyl)propionamide; N-Hydroxy-2-hydroxy-2-(1-methylhydantoin-3-yl)methyl-3-[(4-pyrid-4-yl)-benzenesulfonyl)]propionamide; N-Hydroxy-2-hydroxy-2-(1-butylhydantoin-3-yl)methyl-3-[4-(pyrid-4-yl)-benzenesulfonyl]propionamide; N-Hydroxy-2-hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-[4-pyrid-4-yl)benzenesulfonyl]propionamide; N-Hydroxy-2-hydroxy-2-(phenylthio)methyl-3-[4-(pyrid-4-yl)benzenesulfonyl]propionamide; N- Hydroxy-2-hydroxy-2-(benzylthio)methyl -3-[4-(pyrid-4-yl)benzenesulfonyl]propionamide; N-Hydroxy-2-hydroxy-2-(2-benzylthio-2-methylethyl)-3-[4-(pyrid-4-yl)-benzenesulfonyl]propionamide; N-Hydroxy-2-hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-[4-pyrid-4-yl)oxybenzenesulfonyl]propionamide or N-Hydroxy-2-hydroxy-2-(benzylthio)methyl-3-[4-(pyrid-4-yl)oxybenzenesulfonyi]pripionamide. 2-phenylcarbonyl ethyl, isopropylcarbonyl, methoxycarbonyl, ethoxycarbonyl, 1,1-ethoxycarbonyl methyl, 2,2-ethoxycarbonyl ethyl, 1,2-ethoxycarbonyl ethyl, 2-methoxycarbonyl propyl, 3-methoxycarbonyl propyl, 1-ethoxycarbonyl methyl, 1-ethoxycarbonyl ethyl, phenylcarbonyl, phenylcarbonyl methyl, pyridylcarbonyl methyl, pyridylmethyl, pyridylethyl, quionlinylmethyl, pyrrolyl methyl, indolyl methyl, thienyl, thiazolyl, thienylmethyl, thienylethyl, piperdinyl methyl, piperazinyl methyl, morpholino methyl, morpholino ethyl, morpholino propyl, thiomorpholino methyl, thiomorpholino propyl, 4-methoxybenzenesulfonyl methyl, 3-(4-methoxybenzenesulfonyl)amino propyl, 3-(4-methoxybenzenesulfonyl)propyl, 3-hydroxy, amino, 3-phenoxy propyl, 2-phenyl ethyloxy, (4-butoxybenzenesulfonyl) methyl, methyl-3-(1,5,5-trimethylhydantoin), methyl-3-(1-butyl-5,5-dimethylhydantoin), (4-methoxybenzenesulfonyl)methyl, (4-chlorobenzenesulfonyl)-methyl, (4-bromobenzenesulfonyl)methyl, (n-butylsulfonyl)methyl, (n-octylsulfonyl)-methyl, 3-(4-methoxybenzenesulfonyl)propyl, (4-methylbenzenesulfonyl)methyl, (benzenesulfonyl)methyl, (4-phenylbenzenesulfonyl)methyl, (4-n-butylphenylsulfonyl)methyl, methyl-3-(1-methylhydantoin), methyl-3-(1-butylhydantoin), methyl-3-(5,5-dimethylhydantoin), benzenecarbonylamino or cyclopentanylcarbonylamino. More preferably R2 is (4-methoxybenzenesulfonyl)-methyl, (4-fluorobenzenesulfonyl)methyl, (4-phenylbenzenesulfonyl)methyl, (4-n-butylphenylsulfonyl)methyl, benzenecarbonylamino or cyclopentanylcarbonylamino piperazinyl-methyl,4-(methanesulfonyl)piperazinylmethyl, morpholinomethyl, (1-methylhydantoin-3-yl)methyl,(1,5,5-trimethylhydantoin-3-yl)methyl, (1-butylhylhydantoin-3-yl)methyl, 2-(1-methyl-hydantoin-3-yl)methyl-3-methylethyl, phenylthiomethyl, (2-methoxy)phenylthiomethyl, benzylthiomethyl, (pyrid-2-yl)thiomethyl, (pyrid-2-yl)methylthiomethyl, (5-methylisoxazol-3-yl)thiomethyl, (5-methylisoxazol-3-yl)methylthiomethyl, 2-benzylthio-2-methylethyl, 2-(pyrid-2-yl)methylthio-2-methyl-ethyl, 2-(1-methyl-1H-imidazol-2-yl)methylthio-3-methylethyl, 2-(1-benzyl-1H-imidazol-2-yl)methylthio-2-methylethyl, and 2-(5-methylisoxazol-3-yl)methylthio-2-methylethyl
Y is preferably a hydroxy group.
Examples of the compounds of this invention are as follows:
a. N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-phenylbenzenesulfonyl)-propionamide,
b. N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-fluorobenzenesulfonyl)-propionamide,
C. N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-n-butylbenzenesulfonyl)-propionamide,
d. N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-methoxybenzenesulfonyl)-propionamide,
e. N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(N-benzenecarbonylamino)-propionamide,
f. N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-[N-(cyclopentylcarbonyl)amino]-propionamide, or
g. N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl) methyl]-3-(N-(4-methoxybenzenecarbonyl)amino)-propionamide.
The compounds of this invention can be prepared in accordance to the process discussed below.
In Scheme I, R1 and R2 are the groups as defmed previously. Substituted malonate esters 2 are either obtained commercially, or can be readily prepared from structure 1 by methods well known to those skilled in the art. For example, reaction of an enolate of structure 1, generated by an appropriate base in an appropriate solvent, with an alkylating agent R2-I (I is bromo, chloro, tosylate, mesylate, epoxides, etc.) provides the desired substituted malonate esters 2. See: Organic Synthesis, Vol. 1, p 50 (1954); Organic Synthesis, Vol. 3, p 495 (1955). Compound 2 is hydrolyzed to mono-acid compound 3 by reaction with one equivalent of an appropriate base such as alkali hydroxide in an appropriate solvent at a temperature ranging from 0xc2x0 C. to 30xc2x0 C. In the presence of formaldehyde and piperidine in an appropriate solvent such as pyridine, ethanol, dioxane at refluxing temperatures, compound 3 is converted to acrylic esters 4. In many cases, acrylic esters 4 are commercially available. Acrylic esters 4 may be converted to glycidic esters 5 by oxidation with meta-chloroperoxybenzoic acid (MCPBA) in refluxing ethylene dichloride in the presence of a radical inhibitor such as 4,4xe2x80x2-thiobis-(6-t-butyl-3-methyl-phenol). See: J.C.S.Chem.Comm., pp 64-65 (1972). A thiol (H-SR1) is added to the glycidic ester 5 at room temperature to afford sulfide esters 6 in the presence of a base such as sodium hydride in dry THF, or potassium carbonate in toluene, or a tertiary amine in chloroform. The resultant sulfides 6 are readily oxidized to sulfones 7 by an oxidizing agent such as MCPBA in an appropriate solvent such as methylene chloride, or using hydrogen peroxide in acetic acid as solvent. Alternatively, glycidic esters 5 may be converted to sulfones 7 directly by reaction with sodium sulfinate salts in solvents such as DMF or toluene. The esters can be hydrolyzed by procedures well known in the art such as using 6N HCl and refluxing for 10 to 20 hours or using iodotrimethylsilane in chloroform, or by saponification with aqueous alkali in alcoholic solvents at 0xc2x0 C. to room temperature, to afford free acids 8. Coupling of acids 8 with hydroxylamine hydrochloride to form hydroxamates 10 may be achieved by several routes well known to those skilled in the art. For example, acids 8 can be activated by chloroethylformate in dry THF or a similar compatible solvent, or by a carbodiimide condensing agent such as EDC, with or without HOBT, in DMF and methylene chloride. A tertiary amine is required in both situations. The subsequent reaction of activated 8 with hydroxylamine provides the desired hydroxamic acid derivatives. Alternatively, acids 8 may be condensed, using the same reagents as described above, or using two equivalents of EDC in aqueous THF, with benzyl-protected hydroxylamine hydrochloride, to produce the protected hydroxamates 9. Compounds 9 are often easier to purify, and may readily be hydrogenolytically cleaved to the free hydroxamates 10 by a palladium catalyst in alcoholic solvents. Other protected hydroxylamines, such as tert-butyl hydroxylamine may also be used, and the free hydroxamric acid can be obtained by treating it with trifluoroacetic acid.
A second method of preparing the compounds of the invention particularly applicable to compounds of formula I wherein the R2 group contains heteroatoms is to utilize commercially available bromomethyl acrylic acid esters such as 11, as shown in Scheme II. Treatment of 11 with thiols affords compounds 12. The reaction may be accomplished in dioxane, ethanol, toluene, or other appropriate solvent, at room temperature or reflux, with a base such as sodium bicarbonate or piperidine. See: Annelen, Vol. 564, pp 73-78 (1949). Ester 11 may also be converted directly to the sulfone 13 by treatment with sodium suffinate salts in DMF, toluene, methanol, or other appropriate solvent at room temperature or reflux, with or without sodium iodide as catalyst. See: Tetrahedron Lett., Vol. 28, pp 813-816 (1987). Sulfides 12 or sulfones 13 can be oxidized to glycidic esters 14 by oxidation with a sufficient amount of MCPBA in refluxing ethylene dichloride in the presence of a radical inhibitor such as 4,4xe2x80x2-thiobis-(6-t-butyl-3-methyl-phenol), as referenced above. The glycidic esters 14 may be reacted with nucleophilic compounds Wxe2x80x94H or alkaline salts thereof (wherein W is a group attached via a heteroatom such as oxygen, nitrogen, sulfuir, or halogen) to afford the xcex1-hydroxy esters 7 (R2=CH2xe2x80x94W). These reactions may be accomplished in methanol, DMF, toluene, or other appropriate solvents at room temperature or reflux. See: Tetrahedron, Vol. 51, pp 11841-11854 (1995) for an example of this reaction. Nucleophilic addition to glycidic esters may be facilitated by coordinating ions such as Mg2+or other species such as titanium alkoxides. See: Tetrahedron Lett., Vol. 28, pp 4435-4436 (1987) and J. Org. Chem., Vol. 50, pp 1560-1563 (1985). Comrpounds 7 may be converted to hydroxamic acids 10 according to the methods described in Scheme I. Alternatively, bromomethyl acrylic acid esters 11 may be reacted first with nucleophiles Wxe2x80x94H or alkaline salts thereof under the above-described conditions to afford acrylic esters 4, wherein R2 is xe2x80x94CH2W. Compounds 4 can be converted to hydroxamic acids 10, wherein R2 is xe2x80x94CH2W, according to the procedures described for Scheme I.
Scheme III illustrates the special case of Scheme II wherein glycidic ester 14 is reacted with a thiol or thiolate, as the nucleophile Wxe2x80x94H or its alkaline salt, to afford the xcex1-hydroxy esters 7 (R2=xe2x80x94CH2xe2x80x94Sxe2x80x94R4). The reaction may be accomplished in THF, toluene, or other appropriate solvent, with the thiol and an appropriate base such as sodium hydride or potassium carbonate, at room temperature or reflux. These esters may be oxidized to the bis-sulfone esters 15 with MCPBA in methylene chloride, or hydrogen peroxide in acetic acid. Alternatively, the bis-sulfone esters 15 may be prepared directly from glycidic esters 14 by reaction with the sodium sulfinate salts in DMF, toluene, methanol, or other appropriate solvent at room temperature or reflux, with or without sodium iodide as catalyst. Hydrolysis of bis-sulfone esters 15 to the carboxylic acids 8 (R2=xe2x80x94CH2xe2x80x94S(O)2xe2x80x94R4), and subsequent conversion to hydroxamic acids 10 (R2=xe2x80x94CH2xe2x80x94S(O)2xe2x80x94R4), may be accomplished in accordance with the methods described in Scheme 1. In the special case wherein R1 is the same as R4, the resulting hydroxamic acids are achiral molecules.
Another variation of Scheme II is shown in Scheme IV, wherein glycidic ester is reacted with a nitrile compound R3CN in the presence of an acidic catalyst, preferably boron trifluoride etherate in methylene chloride, to afford the oxazoline esters 16. See: Recueil des Travaux Chimiques des Pays-Bas, Vol. 111, pp 69-74 (1992). The reaction is accomplished in several days at room temperature. The oxazoline esters 16 are hydrolyzed to the xcex1-hydroxy esters 7 (R2=xe2x80x94CH2xe2x80x94NHCOR3) in the presence of acids, preferably oxalic acid in refluxing ethanol. Subsequent conversion of the esters 7 to the hydroxamic acids 10 (R2 =xe2x80x94CH2xe2x80x94NHCOR3) is accomplished by the methods described in Scheme I.
Scheme V illustrates a method whereby compounds of this invention having a heterocyclic moiety may be prepared. Glycidic esters 14 may be reacted with t-butoxycarbonyl (Boc)-protected aminoacrylonitrile, for example, according to the methods of Scheme IV, to afford initially the oxazoline esters 17, and then the xcex1-hydroxy esters 18 (R2=xe2x80x94CH2xe2x80x94NHCOCH2NHBoc). Deprotection of the Boc group with trifluoroacetic acid, followed by reaction of the amine with an acylating agent such as ethyl chloroformate in a solvent such as methylene chloride in the presence of a tertiary amine base such as triethylamine, and subsequent intramolecular acylation of the amide nitrogen may be utilized to afford compounds 19, containing, for example, a hydantoin ring. Conversion of compounds 19 to hydroxamic acids 20 may be accomplished by the methods described in Scheme I. By similar reactions well known in the art, and utilizing other readily available nitrile derivatives and acylating or alkylating agents, compounds 19 containing other nitrogen heterocycles can be prepared, and converted to compounds of this invention.
Scheme VI describes a method of preparing compounds of formula I, wherein Y=xe2x80x94NH2 or xe2x80x94NHR9, via the glycidic esters 5. Thus reaction of glycidic esters 5 with sodium azide in aqueous ethanol affords the azido alcohols 21. Refluxing the azido alcohols with triphenylphosphine in acetonitrile generates the aziridines 22. The aziridines undergo ring opening with thiol HSR1 (followed by oxidation to the sulfone with MCPBA) or with sulfinate salts directly to afford the xcex1-amino esters 23. This reaction may be aided by using boron trifluoride etherate as a Lewis acid catalyst, in methylene chloride. See: J. Org. Chem., Vol. 60, p 790 (1995). Compounds 23 may be converted to the amino acids 24, and thence to hydroxamates 25 by the methods described in Scheme I. The amino group of compounds 22, 23, 24, or 25 may be protected by a Boc group or other amino-protecting group by methods well known to those skilled in the art.
The preparation of compounds of formula I wherein Y=F can be accomplished by the methods shown in Scheme VII. The xcex1-hydroxy esters 7 may be converted to the a-fluoro esters 26 by use of diethylaminosulfur trifluoride (DAST) in a solvent such as methylene chloride at 0xc2x0 C. to room temperature. See: J. Org. Chem., Vol. 40, p 574 (1975). Compounds 26 may be converted to the xcex1-fluoro hydroxamic acids 27 by the methods described in Scheme I.
The chemistry in Schemes I-VII proceeds through achiral or racemic intermediates and pure enantiomers of the final products may be obtained by resolution of intermediates 5-9, 14-19, 21-24, or 26 or final products 10, 20, 25, or 27 by chiral chromatography or by classical derivatization methods such as chiral salt formation of carboxylic acid intermediates such as 8 or 24.
The present invention also provides novel compounds of formula 8 
or pharmaceutical acceptable salts thereof wherein R1, R2 and Y are as defined above. Examples of the compounds of formula 8 are as follows:
2-Hydroxy-2-(1-butylhydantoin-3-yl)methyl-3-(4-butoxybenzenesulfonyl)propionic acid;
2-Hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-(4-butoxybenzenesulfonyl)propionic acid;
2-Hydroxy-2-(phenylthio)methyl-3-(4-butoxybenzenesulfonyl)propionic acid;
2-Hydroxy-2-(benzylthio)methyl-3-(4-butoxybenzenesulfonyl)propionic acid;
2-Hydroxy-2-(2-benzylthio-2-methylethyl)-3-(4-butoxy-benzenesulfonyl)propionic acid;
2-Hydroxy-2-(1-methylhydantoin-3-yl)methyl-3-(4-chloro-biphenylsulfonyl)propionic acid;
2-Hydroxy-2-(1-butylhydantoin-3-yl)methyl-3-(4-chloro-biphenylsulfonyl)propionic acid;
2-Hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-(4-chlorobiphenylsulfonyl)propionic acid;
2-Hydroxy-2-(phenylthio)methyl-3-(4-chlorobiphenyl-sulfonyl)propionic acid;
2-Hydroxy-2-(benzylthio)methyl-3-(4-chlorobiphenyl-sulfonyl)propionic acid;
2-Hydroxy-2-(pyrid-2-yl)thiomethyl-3-(4-chlorobiphenyl-sulfonyl)propionic acid;
2-Hydroxy-2-(5-methylisoxazol-3-yl)methylthiomethyl-3-(4-chlorobiphenylsulfonyl)propionic acid;
2-Hydroxy-2-[2-(1-methylhydantoin-3-yl)-2-methylethyl]-3-(4-chlorobiphenylsulfonyl)propionic acid;
2-Hydroxy-2-(2-benzylthio-2-methylethyl)-3-(4-chloro-biphenylsulfonyl)propionic acid;
2-Hydroxy-2-(1-methylhydantoin-3-yl)methyl-3-(4-phenoxy-benzenesulfonyl)propionic acid;
2-Hydroxy-2-(1-butylhydantoin-3-yl)methyl-3-(4-phenoxy-benzenesulfonyl)propionic acid;
2-Hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-(4-phenoxybenzenesulfonyl)propionic acid;
2-Hydroxy-2-(phenylthio)methyl-3-(4-phenoxybenzene-sulfonyl)propionic acid;
2-Hydroxy-2-(benzylthio)methyl-3-(4-phenoxybenzene-sulfonyl)propionic acid;
2-Hydroxy-2-[2-(1-methylhydantoin-3-yl)-2-methylethyl]-3-(4-phenoxybenzenesulfonyl)propionic acid;
2-Hydroxy-2-[2-(1-methyl-1H-imidazol-2-yl)thio-2-methyl-ethyl]-(4-phenoxybenzenesulfonyl)propionic acid;
2-Hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-[4-(pyrid-4-yl)benzenesulfonyl]propionic acid;
2-Hydroxy-2-(phenylthio)methyl-3-[4-(pyrid-4-yl)benzene-sulfonyl]propionic acid;
2-Hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-[4-(pyrid-4-yl)oxybenzenesulfonyl]propionic acid.
The pharmaceutical compositions of this invention may be prepared by combining the compounds of formula I of this invention with a solid or liquid pharmaceutically acceptable carrier, and optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques. Solid form compositions include powders, tablets, dispersible granules, capsules and suppositories. A solid carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like. Liquid form compositions include solutions, suspensions and emulsions. For example, there may be provided solutions of the compounds of this invention dissolved in water, water-propylene glycol, and water-polyethylene glycol systems, optionally containing conventional coloring agents, flavoring agents, stabilizers and thickening agents.
The pharmaceutical composition is provided by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula I according to this invention.
The quantity of active component, that is the compounds of formula I according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
In therapeutic use for treating a patient, suffering from or susceptible to diseases involving connective tissue degradation, or inhibiting various enzymes from the matrix metalloproteinase family, including collagenase, stromelysin, and gelatinase, the compounds or pharmaceutical compositions thereof will be administered orally, parenterally and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level of active component in the patient undergoing treatment which will be effective to inhibit such enzymes. Generally, an effective amount of the active compound will be in the range of about 0.1 to about 100 mg/kg. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of connective tissue degradation being treated, and the particular compounds being used. Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day.
The compounds of the present invention inhibit various enzymes from the matrix metalloproteinase family, predominantly stromelysin and gelatinase, and hence are useful for the treatment of matrix metallo endoproteinase diseases such as osteoarthritis, rheumatoid arthritis, septic arthritis, osteopenias such as osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulceration, dermal ulceration, gastric ulceration, inflammation, asthma and other diseases related to connective tissue degradation. Such diseases and conditions are well known and readily diagnosed by physician of ordinary skill.
Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compounds according to formula I as a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as; for example, water-for-irection and a suitably buffered isotonic solution having a pH of about 3.5-6. Suitable buffering agents include; for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine, to name a few. The compounds according to formula I generally will be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg/ml to about 400 mg/ml. The resulting liquid pharmaceutical composition will be administered so as to obtain the above-mentioned inhibitory effective amount of dosage. The compounds of formula I according to this invention are advantageously administered orally in solid and liquid dosage forms.